OPEN-CTO Registry Update Dr James Sapontis MonashHeart Melbourne, Australia.

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Grant/Research Support Consulting Fees/Honoraria Major Stock Shareholder/Equity Royalty Income Ownership/Founder Intellectual Property Rights Other Financial Benefit None Boston Scientific, St Jude medical

Increasing numbers of CTO-PCI 2011 2,375 CTOs* 62 centers 15 centers > 50 cases* 2012 5,208 CTOs* 127 centers 33 centers > 50 cases* With the increasing up take of CTO PCI across the world there has been a constant push towards providing objective evidence that this form of treatment can be both safe, efficient and provide significant symptomatic benefits. 58 centers projected > 50 cases* 9,024 CTOs* 241 centers 2013 Projected 2014 124 centers >50 cases *Industry estimate. Data on file as BSCI

The Hybrid Approach PCI Systematic and easily teachable. Adoption of four strategies. Sequence based on probability of success. Rapid decision making and transition. In an attempt to simplify a once thought upon complicated intervention the Hybrid algorithm was invented. It basis was a systematic and easily teachable method of tackling CTO based of four strategies. This technique was aimed at a efficient, systematic, teachable method of achieving success in CTO-PCI. Brilakis et al J Am Coll Cardiol Intv 2012;5:367–79

Four things determine how many and which option to begin with The Hybrid Algorithm Four things determine how many and which option to begin with 1. Proximal Cap Anatomy Defined or Ambiguous? 2. Target Favorable for reentry? 3. Collaterals Useable or not? 4. Occlusion length <20mm or ≥20mm? Direction It focuses on four angiographic variables to determine a strategic approach to CTO PCI incorporating both direction (Antegrade/Retrograde) and crossing strategy. Nevertheless despite the wide adaptation of this simplified method of CTO-PCI there had not been a rigorous evaluation of its overall success, safety, efficiency and outcomes. There are many registries exploring CTO-PCI however, they have been criticized in the past for failure to offer a robust system of analysis. Registries have been plagued with selection bias, physician focused reporting of angiographic outcomes, and complications. There was a need to provide a truly consecutive registry with an angiographic core lab and CEC adjudication of events in order to give a further accurate synopsis of the success, safety and outcomes related to Hybrid CTO-PCI. Crossing strategy

PI James Aaron Grantham. Co PIs James Sapontis, Bill Lombardi Manager Karen Nugent Statistician Kensey Gosch Core Lab Federico Gallegos Publications Spertus, Cohen, Marso, Yeh, McCabe, Grantham, Karmpaliotis To further address these concers of others and assure them of the highest quality data to date we designed the OPEN CTO Trial

OPEN CTO Design 1000 consecutive patients enrolled at 12 clinical sites in the US DESIGN: Prospective, non-randomized, single-arm, multi-center clinical evaluation of the Hybrid CTO-PCI OBJECTIVE: To evaluate the Success, safety, efficiency, appropriateness, health status outcomes, and costs of CTO-PCI PRINCIPAL INVESTIGATOR J. Aaron Grantham, MD, FACC Saint Luke’s Mid America Heart Institute, Kansas City, Mo. USA Comprehensive baseline clinical, angiographic, and HS assessment Clinical follow-up at 1,6, 12 months This is a prospective non-randomized single arm multi-center evaluation of Hybrid CTO-PCI. Success Failure Angina Dyspnea Efficient Inefficient Complicated Uncomplicated

OPEN CTO Sites PeaceHealth St. Joseph Med. Ctr. Bellingham, WA Alexian Brothers Medical Center Elk Grove Village, IL Saint Luke’s Hospital Mid America Heart Institute Kansas City, MO U. Washington Seattle, WA Columbia University Medical Center NY, NY PeaceHealth Sacred Heart Med. Ctr Springfield, OR York Hospital York, PA . Torrance Medical Center Torrance, CA Banner Health System Phoenix and Mesa, AZ Boone Hospital Center Columbia, MO Presbyterian Hospital/ Heart Group Albuquerque, NM

Strengths of OPEN CTO Auditing through NCDR Truly consecutive, funded, unselected, fully reported Angiographic core lab analysis Unbiased QCA Centralized call center follow up (92% at 6 months) CEC adjudication Broad spectrum of operators using a single methodological approach Give detailed economic analysis. The 1 month results of this investigation have been presented before at TCT “late breaking trials”. Today I would like to reveal the 6 month follow up outcomes and some more information.

Enrollment by Site No operator contributed more than 20% or less than roughly 5% of the case load of 1000 patients. All were experienced Hybrid operators with at least over 100 cases

Baseline Patient Characteristics % Age (yrs) 65.4 ± 10.3 Male sex 80.2 BMI (Kg/m2 BSA) 30.8 ± 9.1 White Caucasian 90 Smoking (ever) 64.5 Diabetes 41.4  Hypertension 86.9 Prior MI 48.4  Prior CABG 36.9  Prior PCI 66.0  Prior CHF 22.6  PAD 17.4  CKD>stage 1 13.3  EF (mean) 51.1 ± 13.7% Patient Characteristic % NYHA Class I 8.3 II 40.2 III 43.9 IV 7.6 Stable Angina 91.8 CCSC I 4.2 CCSC II 23.4 CCSC III 56.9 CCSC IV 15.5 Unstable Angina: 8.1 TIMI Score (mean) 2.4 ± 0.6 Seen By Cardiothoracic Surgery 10.2 Suitable for Surgery 35.6 In terms of patient characteristics we can see that the majority of patients were large white American males. The prevalence of diabetes and previous CABG is in the same ball park as previous registries, of around 35-40%. The average EF and incidence of CKD are within in keeping of previous registries. Most with heart failure had either type II / III and the majority of paitent’s with symptoms of angina had siginificant CCSC III. Of note around a third of patients were actually deemed suitable for surgery, and 1 in 10 had been seen by a surgeon.

Physician Assessment One of the aspects of this registry was to determine physicians assessment of the patient and their symptoms and further evaluation of the risk of the CTO. We can see here that the main reason for CTO-PCI was as expected symptoms. But of note also all those that had non-invasive testing, which is the majority, showed evidence of a high ischemic burden in the territory of the CTO-PCI which is likely to have driven AUC

Appropriate Use Criteria 719 Mapped vs 281 Unmapped 28.1% Unmapped No CCS No Non-invasive testing Very few patients (68) had low risk non-invasive testing Going back to Aaron’s talk about indications. Appropriate Use Criteria (AUC) specify when it is appropriate to perform a medical procedure or service. An “appropriate” procedure is one for which the expected health benefits exceed the expected health risks by a wide margin. You can see that the vast majority of patients included in this registry have a good indication or are “apprpriate” for CTO-PCI. 72% of all patients were able to be mapped and the vast majority of those were deemed appropriate according to the AUC criteria.

Angiographic Characteristics % CTO only (%) 86.2 Complete Revasc (%) 82.3 Target Vessel RCA (%) 60.5 LAD (%) 19.6 LCX (%) 13.3 Occlusion Length (mm) 29.9 ± 24.3 Length>20 mm (%) 54.8 Total lesion length (mm) 63.4 ± 28.6 JCTO score <3 (%) 81.2 JCTO score ≥3 (%) 19.7 Angiographic Characteristic % Mean stent length 75.6 + 33.33 Lesion type De novo 90.6 In Stent Restenosis 9.4 Prior Bypass to This Vessel 30 Previously Attempted 22.4 Investment Procedure 8.8 Angiographic characteristics show a standard occlusion length of 30 mm which once again is unanimous amongst a lot of CTO registries. BUT of note the JCTO score was actually less than 3 in over 80% of patients. Which is really interesting as the JCTO which is usually reported by physicians is now being reported by the core lab, this may indicate a little bit of over reporting previously. We can see that the score is still under 3 even with previous attempts which would contribute 1 point.

Overall Results 89% 265 ± 194 ml 120 ± 72 min 2.5 ± 1.9 Gy Almost identical to previous US studies, success is 89% (previous reports of 90-92%), time of 120 and 2.5 Gy which is a little lower than say the PROGRESS registry. 265 ± 194 ml 120 ± 72 min 2.5 ± 1.9 Gy

Procedural Time Breakdown Time between insertion of a device into catheter and crossing into true lumen Time between local and crossing into distal true lumen Time between local and insertion of a device into catheter Procedural time break down is another unique aspect of OPEN. CTO-PCI is often labeled as a time expensive procedure, and we know that it is, over conventional PCI. However, when some consider this it is thought that this was due to crossing the lesion, but this break down shows, on average it takes 20 minutes to get the catheters in and set up shots done. Also just over an hour to cross the lesion from need to skin time and then another 50 minutes after crossing the lesion to actually finish the case, which includes pre-dilation, stent insertion etc. So just under half of the time is really spent on the procedure post crossing which would likely include externalization, pre-dilation, and stenting.

Hybrid Algorithm Adaptation An almost unanimous adoption of the Hybrid approach here

Hybrid Approach Success rate 58% Success rate 55% AWE 12% RDR 24% RWE 13% AWE 55% ADR 44% RWE 21% ADR 14% Success rate 58% Success rate 55%

Equipment Use General Equipment (% per 1000) Per case Sheaths 3±1.3 Guides 3.2±1.0 Guidewires 9.6±6.2 Balloons 4.9±3.0 Corsair (83%) 1.6±0.9 Fine Cross (10%) 1.2±0.5 Peripheral Equipment Rota-blator (6%) 1.8±1.7 burrs Guideliner (36%) Laser (14%) 1.1±0.3 Covered stents (4%) 2.3±0.9 Coils (0.4%) 1.5±1 The most successful and I would say favorite crossing wire of the US is the Pilot, seen not only in OPEN but other registries, however, the Confianza is playing a bigger role here as well compared to previous registries which showed a preference of fielder XT after the pilot. I included this for interest sake. On average 9-10 wires per case, 5 balloons and just under 2 corsairs – and of interest 14% laser usage which is far greater than previous, is the laser now a regular in the US CTO tool box?

Health Status Changes Here is the important stuff, in TCT we showed a significant (statistical significant) difference in health status outcomes before and after successful CTO PCI. We see the SAQ which is a common HS assessment tool showing an improvement ( which is an increase in score, 0 being the poorest result and 100 being healthiest result). This improvement is large within the first month and maintained to 6 months

A decrease in score represents improvement in symptoms Health Status Changes This is also seen with reduction of dyspnea and depression with improvement in both of those at 1 month persisting to 6 months. A decrease in score represents improvement in symptoms

Safety Not Adjudicated In Hospital Frequency Death 0.9%* MI 2.4% Emergent surgery 0.6% Perforation 6.0% Clinical perforation 4.9% (82%) Bleeding Access 4.0% Radiation injury 0.1% 30 Day Frequency Death 1.3% Rehospitalization 14.7% Unplanned 12.1% (82%) Revascularization 2.6% Planned PCI 2.3% CABG 0.3% Skin change 3.1% 6 Month Frequency Death 2.8% Rehospitalization 32.65% Skin change 3.4% Not Adjudicated Safety showed some interesting facts. We found that there was a slightly higher incidence of in–hospital death rates. Even though if you compare this to large volume registries like the NY PCI registry which has 0.6% its not that high, but compared to other CTO-PCI registries where figures are close to 0.2-0.3% there is a large difference. This may indicate less selection and reporting bias. *STS risk estimate for OPEN patients 1.67%

Conclusions OPEN has so far shown Hybrid CTO-PCI high technical success reasonable efficiency significant health status improvement HS improvement is maintained over 6 months CTO-PCI risk may be higher than non-CTO-PCI OPEN CTO will provide the most rigorous and reliable assessment of CTO-PCI practice and outcomes to date